Impact of Genetic Ancestry on T-cell Acute Lymphoblastic Leukemia Outcomes.

The influence of genetic ancestry on biology, survival outcomes, and risk stratification in T-cell Acute Lymphoblastic Leukemia (T-ALL) has not been explored. Genetic ancestry was genomically-derived from DNA-based single nucleotide polymorphisms in children and young adults with T-ALL treated on Children's Oncology Group trial AALL0434. We determined associations of genetic ancestry, leukemia genomics and survival outcomes; co-primary outcomes were genomic subtype, pathway alteration, overall survival (OS), and event-free survival (EFS). Among 1309 patients, T-ALL molecular subtypes varied significantly by genetic ancestry, including increased frequency of genomically defined ETP-like, MLLT10, and BCL11B-activated subtypes in patients of African ancestry. In multivariable Cox models adjusting for high-risk subtype and pathways, patients of Admixed American ancestry had superior 5-year EFS/OS compared with European; EFS/OS for patients of African and European ancestry were similar. The prognostic value of five commonly altered T-ALL genes varied by ancestry - including NOTCH1, which was associated with superior OS for patients of European and Admixed American ancestry but non-prognostic among patients of African ancestry. Furthermore, a published five-gene risk classifier accurately risk stratified patients of European ancestry, but misclassified patients of African ancestry. We developed a penalized Cox model which successfully risk stratified patients across ancestries. Overall, 80% of patients had a genomic alteration in at least one gene with differential prognostic impact by genetic ancestry. T-ALL genomics and prognostic associations of genomic alterations vary by genetic ancestry. These data demonstrate the importance of incorporating genetic ancestry into analyses of tumor biology for risk classification algorithms.

Experience of the first adult-focussed undiagnosed disease program in Australia (AHA-UDP): solving rare and puzzling genetic disorders is ageless.

BACKGROUND: Significant recent efforts have facilitated increased access to clinical genetics assessment and genomic sequencing for children with rare diseases in many centres, but there remains a service gap for adults. The Austin Health Adult Undiagnosed Disease Program (AHA-UDP) was designed to complement existing UDP programs that focus on paediatric rare diseases and address an area of unmet diagnostic need for adults with undiagnosed rare conditions in Victoria, Australia. It was conducted at a large Victorian hospital to demonstrate the benefits of bringing genomic techniques currently used predominantly in a research setting into hospital clinical practice, and identify the benefits of enrolling adults with undiagnosed rare diseases into a UDP program. The main objectives were to identify the causal mutation for a variety of diseases of individuals and families enrolled, and to discover novel disease genes. METHODS: Unsolved patients in whom standard genomic diagnostic techniques such as targeted gene panel, exome-wide next generation sequencing, and/or chromosomal microarray, had already been performed were recruited. Genome sequencing and enhanced genomic analysis from the research setting were applied to aid novel gene discovery. RESULTS: In total, 16/50 (32%) families/cases were solved. One or more candidate variants of uncertain significance were detected in 18/50 (36%) families. No candidate variants were identified in 16/50 (32%) families. Two novel disease genes (TOP3B, PRKACB) and two novel genotype-phenotype correlations (NARS, and KMT2C genes) were identified. Three out of eight patients with suspected mosaic tuberous sclerosis complex had their diagnosis confirmed which provided reproductive options for two patients. The utility of confirming diagnoses for patients with mosaic conditions (using high read depth sequencing and ddPCR) was not specifically envisaged at the onset of the project, but the flexibility to offer recruitment and analyses on an as-needed basis proved to be a strength of the AHA-UDP. CONCLUSION: AHA-UDP demonstrates the utility of a UDP approach applying genome sequencing approaches in diagnosing adults with rare diseases who have had uninformative conventional genetic analysis, informing clinical management, recurrence risk, and recommendations for relatives.

Riding the storm: managing cytokine-related toxicities in CAR-T cell therapy.

The advent of chimeric antigen receptor T cells (CAR-T) has been a paradigm shift in cancer immunotherapeutics, with remarkable outcomes reported for a growing catalog of malignancies. While CAR-T are highly effective in multiple diseases, salvaging patients who were considered incurable, they have unique toxicities which can be life-threatening. Understanding the biology and risk factors for these toxicities has led to targeted treatment approaches which can mitigate them successfully. The three toxicities of particular interest are cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and immune effector cell-associated hemophagocytic lymphohistiocytosis (HLH)-like syndrome (IEC-HS). Each of these is characterized by cytokine storm and hyperinflammation; however, they differ mechanistically with regard to the cytokines and immune cells that drive the pathophysiology. We summarize the current state of the field of CAR-T-associated toxicities, focusing on underlying biology and how this informs toxicity management and prevention. We also highlight several emerging agents showing promise in preclinical models and the clinic. Many of these established and emerging agents do not appear to impact the anti-tumor function of CAR-T, opening the door to additional and wider CAR-T applications.

In Vivo Intra-Articular Antibiotic Concentrations at 24 Hours After TKA Fall Below the Minimum Inhibitory Concentration for Most Bacteria: A Randomized Study of Commercially Available Bone Cement.

BACKGROUND: The use of antibiotic-loaded bone cement (ALBC) to help reduce the risk of infection after primary total knee arthroplasty (TKA) is controversial. There is a paucity of in vivo data on the elution characteristics of ALBC. We aimed to determine whether the antibiotic concentrations of 2 commercially available ALBCs met the minimum inhibitory concentration (MIC) and minimum biofilm eradication concentration (MBEC) for common infecting organisms. METHODS: Forty-five patients undergoing TKA were randomized to receive 1 of the following: bone cement without antibiotic (the negative control; n = 5), a commercially available formulation containing 1 g of tobramycin (n = 20), or a commercially available formulation containing 0.5 g of gentamicin (n = 20). Intra-articular drains were placed, and fluid was collected at 4 and 24 hours postoperatively. An automated immunoassay measuring antibiotic concentration was performed, and the results were compared against published MIC and MBEC thresholds. RESULTS: The ALBC treatment groups were predominantly of White (65%) or Black (32.5%) race and were 57.5% female and 42.4% male. The mean age (and standard deviation) was 72.6 ± 7.2 years in the gentamicin group and 67.6 ± 7.4 years in the tobramycin group. The mean antibiotic concentration in the tobramycin group was 55.1 ± 37.7 µg/mL at 4 hours and 19.5 ± 13.0 µg/mL at 24 hours, and the mean concentration in the gentamicin group was 38.4 ± 25.4 µg/mL at 4 hours and 17.7 ± 15.4 µg/mL at 24 hours. Time and antibiotic concentration had a negative linear correlation coefficient (r = -0.501). Most of the reference MIC levels were reached at 4 hours. However, at 24 hours, a considerable percentage of patients had concentrations below the MIC for many common pathogens, including Staphylococcus epidermidis (gentamicin: 65% to 100% of patients; tobramycin: 50% to 85%), methicillin-sensitive Staphylococcus aureus (gentamicin: 5% to 90%; tobramycin: 5% to 50%), methicillin-resistant S. aureus (gentamicin: 5% to 65%; tobramycin: 50%), Streptococcus species (gentamicin: 10% to 100%), and Cutibacterium acnes (gentamicin: 10% to 65%; tobramycin: 100%). The aforementioned ranges reflect variation in the MIC among different strains of each organism. Gentamicin concentrations reached MBEC threshold values at 4 hours only for the least virulent strains of S. aureus and Escherichia coli. Tobramycin concentrations did not reach the MBEC threshold for any of the bacteria at either time point. CONCLUSIONS: The elution of antibiotics from commercially available ALBC decreased rapidly following TKA, and only at 4 hours postoperatively did the mean antibiotic concentrations exceed the MIC for most of the pathogens. Use of commercially available ALBC may not provide substantial antimicrobial coverage following TKA. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Comparable Clinical and Functional Outcomes Between Osteochondral Allograft Transplantation and Autologous Chondrocyte Implantation for Articular Cartilage Lesions in the Patellofemoral Joint at a Mean Follow-up of 5 Years.

PURPOSE: To assess clinical outcomes and return to sport (RTS) rates among patients who undergo osteochondral allograft (OCA) transplantation and autologous chondrocyte implantation (ACI) or matrix-induced autologous chondrocyte implantation (MACI), for patellofemoral articular cartilage defects. METHODS: A retrospective review of patients who underwent an OCA or ACI/MACI from 2010 to 2020 was conducted. Patient-reported outcomes collected included visual analog scale for pain/satisfaction, Knee Injury and Osteoarthritis Outcome Score (KOOS), and RTS. The percentage of patients that met the patient acceptable symptom state for KOOS was recorded. Logistic regression was used to identify predictors of worse outcomes. RESULTS: A total of 95 patients were included (78% follow-up) with ACI or MACI performed in 55 cases (57.9%) and OCA in 40 (42.1%). A tibial tubercle osteotomy was the most common concomitant procedure for OCA (66%) and ACI/MACI (98%). Overall, KOOS pain was significantly poorer in OCA than ACI/MACI (74.7, 95% confidence interval 68.1-81.1 vs 83.6, 95% confidence interval 81.3, 88.4, P = .012), whereas the remaining KOOS subscores were nonsignificantly different (all P > .05). Overall, RTS rate was 54%, with no significant difference in return between OCA or ACI/MACI (52% vs 58%, P = .738). There were 26 (27%) reoperations and 5 (5%) graft failures in the entire group. Increasing age was associated with lower satisfaction in OCA and poorer outcomes in ACI/MACI, whereas larger lesion area was associated with lower satisfaction and poorer outcomes in ACI/MACI. CONCLUSIONS: Clinical and functional outcomes were similar in patients who underwent OCA or ACI/MACI for patellofemoral articular cartilage defects at a mean follow-up of 5 years. Patients who received OCA had a greater proportion of degenerative cartilage lesions and, among those with trochlear lesions, reported greater pain at final follow-up than their ACI/MACI counterparts. Overall, increasing age and a larger lesion size were associated with worse patient-reported outcomes. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Decreased "Polar Axis Angle" is Associated With Instability After Total Hip Arthroplasty: A New Method to Assess Functional Component Position on Lateral-Seated Radiographs.

BACKGROUND: Research on hip instability has focused on establishing "safe" ranges of combined component position in supine posture or functional placement of the acetabular component based on the hip-spine relationship. A new angle, the polar axis angle (PAA), of the total hip arthroplasty (THA) components describes the concentricity of both components and can be evaluated in functional positions that confer a greater risk of instability (ie, sitting). The goal of this study was to compare the PAA in functional positions between patients who experienced a postoperative dislocation and a matched control group who did not have a dislocation. METHODS: An institutional database was searched for patients experiencing a dislocation after primary THA. Patients who had postoperative full-length standing and lateral-seatedradiographs were included in the dislocator group. A control group of nondislocator patients was matched 2:1 by age, body mass index, sex, and hip-spine classification. Radiographic measurements of the neck angle, acetabular ante-inclination, and PAA were performed by 2 separate blinded, trained reviewers. RESULTS: The lateral-seated neck angle and lateral-seated PAA measurements were significantly lower in the dislocator groups (n = 37) than the control group (n = 74) (23 versus 33 degrees, P < .001; 74 versus 83 degrees, P = .012, respectively). Significant differences were also observed in changes in the polar axes and neck angles between standing and seated positions (P < .001 and P < .001, respectively). When comparing patients who have mobile spines versus stiff spines within the dislocator group, there were no differences in the acetabular, neck, or PAAs. The effect of neck angle on the PAA showed a linear trend across cohorts. CONCLUSIONS: Patients who experience postoperative instability have a significantly lower PAA on lateral-seated radiographs when matched for age, sex, body mass index, and hip-spine classification. In addition, the lower seated PAA is driven more strongly by decreased functional femoral anteversion, which emphasizes the role of functional femoral version on stability in THA.

Right Ventricular Function on Cardiovascular Magnetic Resonance Imaging and Long-Term Outcomes in Stable Heart Transplant Recipients.

BACKGROUND: In heart transplant recipients, right ventricular (RV) dysfunction may occur for a variety of reasons. Whether RV dysfunction in the stable phase after heart transplantation is associated with long-term adverse outcomes is unknown. We aimed to determine the long-term prognostic significance of RV dysfunction identified on cardiovascular magnetic resonance imaging (CMR) at least 1 year after heart transplantation. METHODS: In consecutive heart transplant recipients who underwent CMR for surveillance, we assessed 2 CMR measures of RV function: RV ejection fraction and RV global longitudinal strain (RVGLS). We investigated associations between RV dysfunction and a composite end point of death or major adverse cardiac events, including retransplantation, nonfatal myocardial infarction, coronary revascularization, and heart failure hospitalization. RESULTS: A total of 257 heart transplant recipients (median age, 59 years; 75% men) who had CMR at a median of 4.3 years after heart transplantation were included. Over a median follow-up of 4.4 years after the CMR, 108 recipients experienced death or major adverse cardiac events. In a multivariable Cox regression analysis adjusted for age, time since transplantation, indication for transplantation, cardiac allograft vasculopathy, history of rejection, and CMR covariates, RV ejection fraction was not associated with the composite end point, but RVGLS was independently associated with the composite end point with a hazard ratio of 1.08 per 1% worsening in RVGLS ([95% CI, 1.00-1.17]; P=0.046). RVGLS provided incremental prognostic value over other variables in multivariable analyses. The association was replicated in subgroups of recipients with normal RV ejection fraction and recipients with late gadolinium enhancement imaging. A similar association was seen with a composite end point of cardiovascular death or major adverse cardiac events. CONCLUSIONS: CMR feature tracking-derived RVGLS assessed at least 1 year after heart transplantation was independently associated with the long-term risk of death or major adverse cardiac events. Future studies should investigate its role in guiding clinical decision-making in heart transplant recipients.

Physical Activity and Incident Obesity Across the Spectrum of Genetic Risk for Obesity.

Importance: Despite consistent public health recommendations, obesity rates in the US continue to increase. Physical activity recommendations do not account for individual genetic variability, increasing risk of obesity. Objective: To use activity, clinical, and genetic data from the All of Us Research Program (AoURP) to explore the association of genetic risk of higher body mass index (BMI) with the level of physical activity needed to reduce incident obesity. Design, Setting, and Participants: In this US population-based retrospective cohort study, participants were enrolled in the AoURP between May 1, 2018, and July 1, 2022. Enrollees in the AoURP who were of European ancestry, owned a personal activity tracking device, and did not have obesity up to 6 months into activity tracking were included in the analysis. Exposure: Physical activity expressed as daily step counts and a polygenic risk score (PRS) for BMI, calculated as weight in kilograms divided by height in meters squared. Main Outcome and Measures: Incident obesity (BMI ≥30). Results: A total of 3124 participants met inclusion criteria. Among 3051 participants with available data, 2216 (73%) were women, and the median age was 52.7 (IQR, 36.4-62.8) years. The total cohort of 3124 participants walked a median of 8326 (IQR, 6499-10 389) steps/d over a median of 5.4 (IQR, 3.4-7.0) years of personal activity tracking. The incidence of obesity over the study period increased from 13% (101 of 781) to 43% (335 of 781) in the lowest and highest PRS quartiles, respectively (P = 1.0 × 10-20). The BMI PRS demonstrated an 81% increase in obesity risk (P = 3.57 × 10-20) while mean step count demonstrated a 43% reduction (P = 5.30 × 10-12) when comparing the 75th and 25th percentiles, respectively. Individuals with a PRS in the 75th percentile would need to walk a mean of 2280 (95% CI, 1680-3310) more steps per day (11 020 total) than those at the 50th percentile to have a comparable risk of obesity. To have a comparable risk of obesity to individuals at the 25th percentile of PRS, those at the 75th percentile with a baseline BMI of 22 would need to walk an additional 3460 steps/d; with a baseline BMI of 24, an additional 4430 steps/d; with a baseline BMI of 26, an additional 5380 steps/d; and with a baseline BMI of 28, an additional 6350 steps/d. Conclusions and Relevance: In this cohort study, the association between daily step count and obesity risk across genetic background and baseline BMI were quantified. Population-based recommendations may underestimate physical activity needed to prevent obesity among those at high genetic risk.

Anterior Cruciate Ligament Allograft Reconstruction Augmented With a Reinforced, Bioinductive Collagen Scaffold in the Setting of Multiligamentous Knee Injury.

The gold standard for surgical treatment of anterior cruciate ligament (ACL) injuries is reconstruction. There are a variety of graft options, from autograft to allograft, using bone-patellar tendon-bone (BTB), hamstrings, quadriceps, or Achilles, and, in the case of a multiligamentous knee injury (MLKI), allograft may be preferred to decrease operative time and graft harvest morbidity. The BioBrace (ConMed, New Haven, CT) is a bioinductive collagen scaffold designed to provide an environment for soft tissue remodeling with time zero biomechanical support and can be used to augment graft reconstructions in the case of concerns for allograft strength, healing, or width. The purpose of this Technical Note is to describe the technique for performing an ACL reconstruction with BioBrace-augmented allograft in the setting of a MLKI, with special consideration for 2 methods of graft preparation (BTB and soft tissue).

Clinical and Functional Outcomes of Documented Knee Dislocation Versus Multiligamentous Knee Injury: A Comparison of KD3 Injuries at Mean 6.5 Years Follow-up.

BACKGROUND: Previous research has found that the incidence of neurovascular injury is greatest among multiligamentous knee injuries (MLKIs) with documented knee dislocation (KD). However, it is unknown whether there is a comparative difference in functional recovery based on evidence of a true dislocation. PURPOSE: To determine whether the knee dislocation-3 (KD3) injury pattern of MLKI with documented tibiofemoral dislocation represents a more severe injury than KD3 MLKI without documented dislocation, as manifested by poorer clinical outcomes at long-term follow-up. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A multicenter retrospective cohort study was performed of patients who underwent surgical treatment for KD3 MLKI between May 2012 and February 2021. Outcomes were assessed using the International Knee Documentation Committee (IKDC) score, Lysholm score, Tegner activity scale, and visual analog scale (VAS) for pain. Documented dislocation was defined as a radiographically confirmed tibiofemoral disarticulation, the equivalent radiology report from outside transfer, or emergency department documentation of a knee reduction maneuver. Subgroup analysis was performed comparing lateral (KD3-L) versus medial (KD3-M) injuries. Multivariable linear regression was conducted to determine whether documented dislocation was predictive of outcomes. RESULTS: A total of 42 patients (25 male, 17 female) were assessed at a mean 6.5-year follow-up (range, 2.1-10.7 years). Twenty patients (47.6%) were found to have a documented KD; they reported significantly lower IKDC (49.9 vs 63.0; P = .043), Lysholm (59.8 vs 74.5; P = .023), and Tegner activity level (2.9 vs 4.7; P = .027) scores than the patients without documented dislocation. VAS pain was not significantly different between groups (36.4 vs 33.5; P = .269). The incidence of neurovascular injury was greater among those with documented dislocation (45.0% vs 13.6%; P = .040). Subgroup analysis found that patients with KD3-L injuries experienced a greater deficit in Tegner activity level than patients with KD3-M injuries (Δ: -3.4 vs -1.2; P = .006) and had an increased incidence of neurovascular injury (41.7% vs 11.1%; P = .042). Documented dislocation status was predictive of poorer IKDC (ß = -2.15; P = .038) and Lysholm (ß = -2.85; P = .007) scores. CONCLUSION: Patients undergoing surgical management of KD3 injuries with true, documented KD had significantly worse clinical and functional outcomes than those with nondislocated joints at a mean 6.5-year follow-up. The current MLKI classification based solely on ligament involvement may be obscuring outcome research by not accounting for true dislocation.

Patients who undergo tibial tubercle anteromedialization with medial patellofemoral ligament reconstruction demonstrate similar rates of return to sport compared to isolated MPFL reconstruction.

PURPOSE: To investigate the rate of return to sports and sport psychological readiness between patients who underwent isolated MPFLR (iMPFLR) compared to a matched cohort of patients who underwent MPFLR with anteromedializing tibial tubercle osteotomy (MPFLR/TTO). METHODS: Patients who underwent primary MPFLR with or without TTO for recurrent patellar instability were retrospectively reviewed from 2012 to 2020 at a single institution. Preinjury sport and work information, Kujala, Tegner, Visual Analogue Score for pain, satisfaction and MPFL-Return to Sport after Injury (MPFL-RSI) score were collected. Two readers independently measured the tibial tuberosity-trochlear groove distance, Caton-Deschamps index and Dejour classification for trochlear dysplasia. Patients in iMPFLR and MPFLR/TTO groups were matched 1:1 on age, sex, body mass index and follow-up length. Multivariate regression analysis was performed to determine whether the MPFL-RSI was associated with a return to sport. RESULTS: This study included 74 patients at mean follow-up of 52.5 months (range: 24-117). These groups returned to sport at similar rates (iMPFLR: 67.6%, MPFLR/TTO: 73.0%, not significant [ns]), though iMPFLR patients returned more quickly (8.4 vs. 12.8 months, p = 0.019). Rates of return to preinjury sport level were also similar (45.9% vs. 40.5%, ns). Patients with Dejour B/C took more time to return to sport compared to patients with mild/no trochlear pathology (13.8 vs. 7.9 months, p = 0.003). Increasing MPFL-RSI score was significantly predictive of the overall return to sport (odds ratio [OR]: 1.08, 95% confidence interval [CI] [1.03, 1.13], p < 0.001) and return to preinjury level (OR: 1.07, 95% CI [1.04, 1.13], p < 0.001). Most patients in iMPFLR and MPFLR/TTO groups resumed work (95.7% vs. 88.5%, ns), though iMPFLR patients who returned to preinjury work levels did so more quickly (1.7 vs. 4.6 months, p = 0.005). CONCLUSION: Patients who underwent MPFLR with anteromedializing TTO demonstrated similar rates of return to sport and psychological readiness compared to an isolated MPFLR matched comparison group, though iMPFLRs returned more quickly. Patients with more severe trochlear pathology required more time to return to sports. LEVEL OF EVIDENCE: Level III.

Patient-reported outcomes and return to pre-injury activities after surgical treatment of multi-ligamentous knee injuries in patients over 40-years-old: Average 5-years follow-up.

BACKGROUND: Multi-ligamentous knee injuries (MLKI) are potentially devastating injuries, though existing prognostic research among older patients who sustain MLKI is limited. The purpose was to investigate clinical outcomes and rates of return to pre-injury activities following surgical treatment of MLKI in patients at least 40 years old. METHODS: This study was a multi-center retrospective case series of patients who underwent surgical treatment for MLKI from 2013-2020 and were ≥ 40 years old at time of injury. Outcomes were assessed via e-mail and telephone using the International Knee Documentation Committee (IKDC) score, Lysholm score, Tegner activity scale, a satisfaction rating, and return to pre-injury sport and work surveys. Stepwise linear regression was used to assess the impact of preoperative characteristics on IKDC and Lysholm scores. RESULTS: Of 45 patients eligible for inclusion, 33 patients (mean age: 48.6 years [range: 40-72]) were assessed at a mean follow-up of 59.1 months (range 24-133). The cohort reported a mean IKDC of 63.4 ± 23.5, Lysholm of 72.6 ± 23.6, and Tegner of 3.8 ± 2.0. There was a 41.2% rate of return to sports, and 82.1% returned to work. Documented knee dislocation was predictive of poorer IKDC (ß:-20.05, p = 0.025) and Lysholm (ß:-19.99, p = 0.030). Patients aged > 50 were more satisfied compared to those 40-50 years old (96.2 ± 4.9 vs 75.6 ± 23.3, p = 0.012). CONCLUSIONS: Patients who sustained MLKI aged at least 40 at injury demonstrated fair clinical outcomes at a mean 5-year follow-up. Older patients who sustained MLKI reported a relatively high rate of return to work but were less likely to return to sports. LEVEL OF EVIDENCE: IV, Case series.

The impact of the COVID-19 pandemic on cardiovascular disease prevention and corresponding geographical inequalities in England: interrupted time series analysis.

BACKGROUND: There has been disruption to the detection and management of those with hypertension and atrial fibrillation (AF) during the COVID-19 pandemic. This is likely to vary geographically and could have implications for future mortality and morbidity. We aimed to estimate the change in diagnosed prevalence, treatment and prescription indicators for AF and hypertension and assess corresponding geographical inequalities. METHODS: Using the Quality and Outcomes Framework (2016/17 to 2021/22) and the English Prescribing Datasets (2018 to 2022), we described age standardised prevalence, treatment and prescription item rates for hypertension and AF by geography and over time. Using an interrupted time-series (ITS) analysis, we estimated the impact of the pandemic (from April 2020) on missed diagnoses and on the percentage change in medicines prescribed for these conditions. Finally, we described changes in treatment indicators against Public Health England 2029 cardiovascular risk targets. RESULTS: We observed 143,822 fewer (-143,822, 95%CI:-226,144, -61,500, p = 0.001) diagnoses of hypertension, 60,330 fewer (-60,330, 95%CI: -83,216, -37,444, p = 0.001) diagnoses of AF and 1.79% fewer (-1.79%, 95%CI: -2.37%, -1.22%), p < 0.0001) prescriptions for these conditions over the COVID-19 impact period. There was substantial variation across geography in England in terms of the indirect impact of the COVID-19 pandemic on the diagnosis, prescription, and treatment rates of hypertension and AF. 20% of Sub Integrated Care Boards account for approximately 62% of all missed diagnoses of hypertension. The percentage of individuals who had their hypertension controlled fell from 75.8% in 2019/20 to 64.1% in 2021/22 and the percentage of individuals with AF who were risk assessed fell from 97.2% to 90.7%. CONCLUSIONS: Hypertension and AF detection and management were disrupted during the COVID-19 pandemic. The disruption varied considerably across diseases and geography. This highlights the utility of administrative and geographically granular datasets to inform targeted efforts to mitigate the indirect impacts of the pandemic through applied secondary prevention measures.

A modified Delphi consensus statement on patellar instability: part I.

Aims: The aim of this study was to establish consensus statements on the diagnosis, nonoperative management, and indications, if any, for medial patellofemoral complex (MPFC) repair in patients with patellar instability, using the modified Delphi approach. Methods: A total of 60 surgeons from 11 countries were invited to develop consensus statements based on their expertise in this area. They were assigned to one of seven working groups defined by subtopics of interest within patellar instability. Consensus was defined as achieving between 80% and 89% agreement, strong consensus was defined as between 90% and 99% agreement, and 100% agreement was considered to be unanimous. Results: Of 27 questions and statements on patellar instability, three achieved unanimous consensus, 14 achieved strong consensus, five achieved consensus, and five did not achieve consensus. Conclusion: The statements that reached unanimous consensus were that an assessment of physeal status is critical for paediatric patients with patellar instability. There was also unanimous consensus on early mobilization and resistance training following nonoperative management once there is no apprehension. The statements that did not achieve consensus were on the importance of immobilization of the knee, the use of orthobiologics in nonoperative management, the indications for MPFC repair, and whether a vastus medialis oblique advancement should be performed.

Sociodemographic and health-related differences in undiagnosed hypertension in the health survey for England 2015-2019: a cross-sectional cohort study.

Background: Hypertension is a leading cause of morbidity and mortality worldwide, yet a substantial proportion of cases are undiagnosed. Understanding the scale of undiagnosed hypertension and identifying groups most at risk is important to inform approaches to detection. Methods: In this cross-sectional cohort study, we used data from the 2015 to 2019 Health Survey for England, an annual, cross-sectional, nationally representative survey. The survey follows a multi-stage stratified probability sampling design, involving a random sample of primary sampling units based on postcode sectors, followed by a random sample of postal addresses within these units. Within each selected household, all adults (aged ≥16 years) and up to four children, were eligible for participation. For the current study, individuals aged 16 years and over who were not pregnant and had valid blood pressure data were included in the analysis. The primary outcome was undiagnosed hypertension, defined by a measured blood pressure of 140/90 mmHg or above but no history of diagnosis. Age-adjusted prevalence of undiagnosed hypertension was estimated across sociodemographic and health-related characteristics, including ethnicity, region, rural-urban classification, relationship status, highest educational qualification, National Statistics Socio-Economic Classification (NS-SEC), Body Mass Index (BMI), self-reported general health, and smoking status. To assess the independent association between undiagnosed hypertension and each characteristic, we fitted a logistic regression model adjusted for sociodemographic factors. Findings: The sample included 21,476 individuals, of whom 55.8% were female and 89.3% reported a White ethnic background. An estimated 30.7% (95% confidence interval 29.0-32.4) of men with hypertension and 27.6% (26.1-29.1) of women with hypertension were undiagnosed. Younger age, lower BMI, and better self-reported general health were associated with an increased likelihood of hypertension being undiagnosed for men and women. Living in rural areas and in regions outside of London and the East of England were also associated with an increased likelihood of hypertension being undiagnosed for men, as were being married or in a civil partnership and having higher educational qualifications for women. Interpretation: Hypertension is commonly undiagnosed, and some of the groups that are at the lowest risk of hypertension are the most likely to be undiagnosed. Given the high lifetime risk of hypertension and its strong links with morbidity and mortality, our findings suggest a need for greater awareness of the potential for undiagnosed hypertension, including among those typically considered 'low risk'. Further research is needed to assess the impact of extending hypertension screening to lower-risk groups. Funding: None.

Cervico-thoracic Morel-Lavallée lesion.

Morel-Lavallée lesions (MLLs) result from high-energy trauma causing separation of subcutaneous tissue from the underlying tissue, most commonly in the gluteal region or thigh.We report the case of a woman in her 40s with a fluctuant collection of the cervico-thoracic region following trauma. Further imaging identified an MLL. An orthoplastic approach resulted in non-operative management with a spinal brace. Three months from initial injury, the lesion completely resolved. She was symptom free at final follow-up and discharged.We present the only recorded case of MLL developing in the cervico-thoracic region. Management posed difficultly as no literature currently exists. We demonstrated conservative management for cervico-thoracic MLL can be effective.We have described the first documented case of cervico-thoracic MLL. MLL is not exclusive to pelvic injuries and can develop in the cervico-thoracic region. We have shown conservative management is a viable treatment of atypical MLL.

A modified Delphi consensus statement on patellar instability: part II.

Aims: The aim of this study was to establish consensus statements on medial patellofemoral ligament (MPFL) reconstruction, anteromedialization tibial tubercle osteotomy, trochleoplasty, and rehabilitation and return to sporting activity in patients with patellar instability, using the modified Delphi process. Methods: This was the second part of a study dealing with these aspects of management in these patients. As in part I, a total of 60 surgeons from 11 countries contributed to the development of consensus statements based on their expertise in this area. They were assigned to one of seven working groups defined by subtopics of interest. Consensus was defined as achieving between 80% and 89% agreement, strong consensus was defined as between 90% and 99% agreement, and 100% agreement was considered unanimous. Results: Of 41 questions and statements on patellar instability, none achieved unanimous consensus, 19 achieved strong consensus, 15 achieved consensus, and seven did not achieve consensus. Conclusion: Most statements reached some degree of consensus, without any achieving unanimous consensus. There was no consensus on the use of anchors in MPFL reconstruction, and the order of fixation of the graft (patella first versus femur first). There was also no consensus on the indications for trochleoplasty or its effect on the viability of the cartilage after elevation of the osteochondral flap. There was also no consensus on postoperative immobilization or weightbearing, or whether paediatric patients should avoid an early return to sport.

Adjusting expected deaths for mortality displacement during the COVID-19 pandemic: a model based counterfactual approach at the level of individuals.

BACKGROUND: Near-real time surveillance of excess mortality has been an essential tool during the COVID-19 pandemic. It remains critical for monitoring mortality as the pandemic wanes, to detect fluctuations in the death rate associated both with the longer-term impact of the pandemic (e.g. infection, containment measures and reduced service provision by the health and other systems) and the responses that followed (e.g. curtailment of containment measures, vaccination and the response of health and other systems to backlogs). Following the relaxing of social distancing regimes and reduction in the availability of testing, across many countries, it becomes critical to measure the impact of COVID-19 infection. However, prolonged periods of mortality in excess of the expected across entire populations has raised doubts over the validity of using unadjusted historic estimates of mortality to calculate the expected numbers of deaths that form the baseline for computing numbers of excess deaths because many individuals died earlier than they would otherwise have done: i.e. their mortality was displaced earlier in time to occur during the pandemic rather than when historic rates predicted. This is also often termed "harvesting" in the literature. METHODS: We present a novel Cox-regression-based methodology using time-dependent covariates to estimate the profile of the increased risk of death across time in individuals who contracted COVID-19 among a population of hip fracture patients in England (N = 98,365). We use these hazards to simulate a distribution of survival times, in the presence of a COVID-19 positive test, and then calculate survival times based on hazard rates without a positive test and use the difference between the medians of these distributions to estimate the number of days a death has been displaced. This methodology is applied at the individual level, rather than the population level to provide a better understanding of the impact of a positive COVID-19 test on the mortality of groups with different vulnerabilities conferred by sociodemographic and health characteristics. Finally, we apply the mortality displacement estimates to adjust estimates of excess mortality using a "ball and urn" model. RESULTS: Among the exemplar population we present an end-to-end application of our methodology to estimate the extent of mortality displacement. A greater proportion of older, male and frailer individuals were subject to significant displacement while the magnitude of displacement was higher in younger females and in individuals with lower frailty: groups who, in the absence of COVID-19, should have had a substantial life expectancy. CONCLUSION: Our results indicate that calculating the expected number of deaths following the first wave of the pandemic in England based solely on historical trends results in an overestimate, and excess mortality will therefore be underestimated. Our findings, using this exemplar dataset are conditional on having experienced a hip fracture, which is not generalisable to the general population. Fractures that impede mobility in the weeks that follow the accident/surgery considerably shorten life expectancy and are in themselves markers of significant frailty. It is therefore important to apply these novel methods to the general population, among whom we anticipate strong patterns in mortality displacement - both in its length and prevalence - by age, sex, frailty and types of comorbidities. This counterfactual method may also be used to investigate a wider range of disruptive population health events. This has important implications for public health monitoring and the interpretation of public health data in England and globally.

Allele-specific quantification of human leukocyte antigen transcript isoforms by nanopore sequencing.

Introduction: While tens of thousands of HLA alleles have been identified by DNA sequencing, the contribution of alternative splicing to HLA diversity is not well characterized. In this study, we sought to determine if long-read sequencing could be used to accurately quantify allele-specific HLA transcripts in primary human lymphocytes. Methods: cDNA libraries were prepared from peripheral blood lymphocytes from 12 donors and sequenced by nanopore long-read sequencing. HLA reads were aligned to donor-specific reference sequences based on the known type of each donor. Allele-specific exon utilization was calculated as the proportion of reads aligning to each allele containing known exons, and transcript isoforms were quantified based on patterns of exon utilization within individual reads. Results: Splice variants were rare among class I HLA genes (median exon retention rate 99%-100%), except for several HLA-C alleles with exon 5 spliced out of up to 15% of reads. Splice variants were also rare among class II HLA genes (median exon retention rate 98%-100%), except for HLA-DQB1. Consistent with previous work, exon 5 of HLA-DQB1 was spliced out in alleles with a mutated splice acceptor site at rs28688207. Surprisingly, a 28% loss of exon 5 was also observed in HLA-DQB1 alleles with an intact splice acceptor site at rs28688207. Discussion: We describe a simple bioinformatic workflow to quantify allele-specific expression of HLA transcript isoforms. Further studies are warranted to characterize the repertoire of HLA transcripts expressed in different cell types and tissues across diverse populations.